Meta analysis

A meta-analysis is the statistical procedure for combining data from multiple studies. When the effect (or effect size) is consistent from one study to the next, a meta-analysis can be used to 

Toxicological Risk Assessments of Chemicals A Practical Guide 

A comprehensive meta-analysis software program has been developed by a team of experts in the United States and the United Kingdom (Borenstein et al. 2005). 

A handbook Meta Analysis The Handbook for the Understanding and Practice of Meta-Analysis and an accompanying program META are available (Leandro 2005). 

6 Meta-analysis, Group Sequential Study Designs, and other topics 

The size and hence geographical distribution of investigational sites needed for the large cardiovascular safety outcome trials discussed in Chap. 13 mean that there can be a considerable degree of variability in the identification of cardiovascular endpoints of interest since classification of events as actual study endpoints is a partially subjective process based on the application of a complex set of medical endpoint criteria to an often complex clinical event. Regulatory agencies therefore require the centralized adjudication of these events to control for the impact of this variability in identification and thereby to generate data for use in statistical analyses that are as standardized as possible. 

Composite endpoints are used in these cardiovascular outcome safety trials since the occurrence of individual events is typically low. The statistical rationale for employment of these endpoints is explained. 

The underlying logic behind meta-analysis is straightforward by creating a larger 

1 More Informative Nomenclature The Term Meta-methodology 

With the launch of dbGaP (Madman et al., 2007), SNP-level results from numerous GWAS can be readdy obtained and jointly analyzed if desired. This opens up the possibility of combined analysis of different datasets for the same disease or similar diseases. Meta-analysis is commonly used in genetic studies to pool results from 

Little drops of water Little grains of sand Make the mighty ocean And the beauteous land 

And the little moments Humble though they be Make the mighty ages Of eternity 

The drop of rain maketh a hole in the stone, not by violence, but by oft falling. 

Hugh Latimer, Seventh Sermon before Edward VI 

There are a number of techniques which may be used. If the studies involved have a similar structure and use the same outcome variables and the meta-analyst has access to the original data (which is usually the situation of the drug developer), then an analysis of these raw data is both possible and (almost invariably) desirable. This has been referred to as a type A meta-analysis (Senn, 2000b). The situation is then very like that in a multicentre trial, with trials rather than centres forming the strata. In principle all the controversies, issues and difficulties which arise with multicentre trials may be attendant on such an analysis but there is no particular reason why new difficulties should present themselves. 

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The issue of whether sperm counts are declining has been the focus of most media attention. A debate still continues as to whether the reported changes in sperm quality are genuine. In 1992, an article described the meta analysis of available data on semen quality in normal men, taken from reports published between the period 1938-1990. This analysis showed a 50% decline in sperm concentration... 

In more recent times, large doses of vitamin C have been claimed to prevent the common cold, cure infertility, delay the onset of symptoms in acquired immunodeficiency syndrome (AIDS), and inhibit the development of gastric and cervical cancers. None of these claims have been backed by medical evidence, however. In the largest study yet done of the effect of vitamin C on the common cojd, a meta-analysis of more than 100 separate trials covering 40,000 people found no difference in the incidence of colds between those who took supplemental vitamin G regularly and those who did not. When taken during a cold, however, vitamin C does appear to decrease the cold s duration by 8%. 

Antiplatetelet Trialists Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324 71-86... 

Cholesterol Treatment Trialists (CTT) Collaborators (2005) Efficacy and safety of cholesterol-lowering treatment prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 366 1267-1278... 

Cannon CP et al (2006) Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 48 438-445... 

A recent meta-analysis of total abstinence as an outcome in clinical trials of acamprosate (Mann et al. 2004) included 17 studies and a total of more than 4,000 patients. The authors found a significant advantage for acampro-... 

Chick et al. (2003) conducted a meta-analysis that included data from 15 studies of acamprosate in an effort to determine whether acamprosate reduces the severity of relapse for patients in abstinence-oriented treatment who fail to abstain completely. Among patients who relapsed to drinking, acamprosate was significantly associated with less quantity and frequency of drinking, compared with placebo, at each of four follow-up periods (i.e., at 30, 90, 180, and 360 treatment days). During each of these periods, there were also fewer acamprosate-treated patients who drank an average of five or more drinks per day. 

Kranzler HR, Van Kirk J Efficacy of naltrexone and acamprosate for alcoholism treatment a meta-analysis. Alcohol Clin Exp Res 23 1335-1341, 2001 Kranzler HR, Babor TF, Lauerman R Problems associated with average alcohol consumption and frequency of intoxication in a medical population. Alcohol Clin Exp Res 14 119-126, 1990... 

Mann K, Lehert P, Morgan MY The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals results of a meta-analysis. Alcohol... 

Streeton C, Whelan G Naltrexone, a relapse prevention maintenance treatment of alcohol dependence a meta-analysis of randomized controlled trials. Alcohol Alcohol 36 544-552, 2001... 

Barker MJ, Greenwood KM, Jackson M, et al Cognitive effects of long-term benzodiazepine use a meta-analysis. CNS Drugs 18 37M8, 2004... 

A meta-analysis of placebo-controlled studies by Levin and Lehman (1991) showed that desipramine produced greater cocaine abstinence than placebo. Although a more recent review did not concur (Lima et al. 2001), secondary analyses of studies with imipramine, desipramine, and bupropion suggested that depressed cocaine abusers are more likely to show significant reductions in cocaine abuse than nondepressed cocaine abusers (Margolin et al. 1995 Nunes et al. 1991 Ziedonis and Kosten 1991). Furthermore, recent work with desipramine supported its efficacy in opioid-dependent patients, particularly in combination with contingency management therapies (Kosten et al. 2004 Oliveto et al. 1999). 

Kranzler HR, Bauer LO, Hersh D, et al Carbamazepine treatment of cocaine dependence a placebo-controlled trial. Drug Alcohol Depend 38 203-211, 1995 Levin FR, Lehman AF Meta-analysis of desipramine an adjunct in the treatment of cocaine addiction. J Clin Pharmacol 11 374-378, 1991 Lima MS, Reisser AA, Soares BG, et al Antidepressants for cocaine dependence. Cochrane Database Syst Rev 4 CD002950, 2001 Ling W, Shoptaw S, Majewska D Baclofen as a cocaine anti-craving medication a preliminary clinical study 0etter). Neuropsychopharmacology 18 403 04, 1998... 

Kranzler HR, Van Kirk J Efficacy of naltrexone and acamprosate for alcoholism treatment a meta-analysis. Alcohol Clin Exp Res 23 1335-1341, 2001... 

Covey LS, Classman AH A meta-analysis of double-blind placebo controlled trials of clonidine for smoking cessation. Br J Addict 86 991—998, 1991 Covey LS, Classman AH, Stetner F Naltrexone effects on short-term and long-term smoking cessation.] Addict Dis 18 31 0, 1999 Covey LS, Sullivan MA, Johnston A, et al Advances in non-nicotine pharmacotherapy for smoking cessation. Drugs 39 17-31, 2000 Dani JA, De Biasi M Cellular mechanisms of nicotine addiction. Pharmacol Biochem Behav 70 439 46, 2001... 

In some pharmacotherapy studies, psychotherapy exposure has been minimized, on the basis of concern that psychotherapy may produce a ceiling effect on improvement in drug or alcohol use, making medication effects difficult to detect. However, a recent meta-analysis revealed that psychosocial interventions, in fact, may enhance pharmacotherapeutic effects (Hopkins et al. 2002). In this review we have also noted instances where psychosocial and medication treatments have had beneficial additive effects. Minimization of psychotherapy in pharmacotherapy trials may be counterproductive, because psychosocial therapies that encourage the patient to remain engaged in treatment may positively affect patients adherence to the medication regimen, a factor that has an effect on alcohol treatment outcomes (Chick et al. 2000 Volpicelli et al. 1997). 

Higgins ST, Sigmon SC, Wong CJ, et al Community reinforcement therapy for cocaine-dependent outpatients. Arch Gen Psychiatry 60 1043—1052, 2003 Hopkins JS, Garbutt JC, Poole CL, et al Naltrexone and acamprosate meta-analysis of two medical treatments for alcoholism. Presented at the 25th annual meeting of the Research Society on Alcoholism, San Francisco, CA, June 28—July 3, 2002... 

Paokolainen K Effectiveness of brief interventions to reduce alcohol intake in primary health care populations a meta-analysis. Prevent Med 28 503-509, 1999... 

This chapter adds the socio-economic dimension to the medical or technical perspectives of the proceeding contributions of this book. As its health economic terminology and approach might be unfamiliar to some readers, we start with a section on methodology. In particular, we present an overview of the concept of Cost-of-Illness (COI) and of relevant health economic evaluation techniques. In Sect. 2, we present the basic findings of a meta-analysis of the socio-economic costs of HIV/AIDS and of the socio-economic impact of antiviral intervention. The major findings are reflected in Sect. 3. The chapter closes with a speculation on long-term socio-economic costs of antiviral intervention. 

Table 2. Prevalence of symptoms in anaphylactic reactions according to Przybilla and Rueff [see 18]. A meta-analysis of 1,865 cases from 14 publications (Liebermann) and 865 own patients with insect venom anaphylaxis... 

Cross-reactions with aspirin and NSAIDs are of practical importance. Typically, AIA patients are sensitive to all NSAIDs that preferentially inhibit COX-1 (table 2). Acetaminophen (paracetamol), a weak inhibitor of COX-1, is regarded as a relatively safe therapeutic alternative for almost all patients with AIA. High doses of the drug (>1,000 mg) have been reported to provoke mild, easily reversed bronchos-pasm in some AIA patients [13]. Some rare, well-documented cases of coexistence of aspirin and paracetamol sensitivity have been described. However, according to a recent meta-analysis, less that 2% of asthmatics are sensitive to both aspirin and paracetamol [14]. 

Strength of recommendation A based on a meta-analysis or at least one randomized controlled trial. Strength of recommendation B based on at least one well-designed study, including case control and comparative studies. Strength of recommendation C based on expert reports or opinion (levels of evidence and strength of recommendation. Oxford (UK) Centre for Evidence-Based Medicine. Available at http //www.cebm.net/levels of evidence.asp (accessed December 8,2008). 

Chang C, Pang KS, Swaan PW, Ekins S. Comparative pharmacophore modeling of organic anion transporting polypeptides a meta-analysis of rat Oatplal and human OATPIBI. J Pharmacol Exp Ther 2005 314 533-41. 

Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients a meta-analysis of prospective studies. JAMA. 1998 Apr 15 279(15) 1200-5. 

Anderson IM, Tomenson BM (1994). The efficacy of selective serotonin reuptake inhibitors in depression a meta-analysis of studies against tricyclic antidepressants. / Psychopharmacol 8, 238 9. 

Gould RA, Otto MW, Pollack MH (1995). A meta analysis of treatment outcome for panic disorder. Clin Psychol Rev 15, 819-44. 

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects. In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects showed that statin therapy reduced the incidence of stroke by 18%, major coronary events by 27%, and all-cause mortality by 15%. The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks. ... 

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